Chemokines Induce Wnt-Frizzled Gene Expression in Human T Cells

趋化因子诱导人类 T 细胞中 Wnt 卷曲基因表达

• 批准号: 8552468
• 负责人: DENNIS D. TAUB
• 金额: $ 26.1万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8552468
• 关键词: Activated B-Lymphocyte; Adhesions; Adrenal Glands; Age; Binding; Biology; Bone Marrow; CCL19 gene; CXCL12 gene; CXCR4 gene; Cells; Cellular biology; Chemotactic Factors; Chemotaxis; Data; Development; Event; Family member; GTP-Binding Proteins; Gene Expression; Gene Family; Glycoproteins; HIV; HIV Envelope Protein gp120; HIV-1; Human; Immigration; Immune; In Vitro; Inflammation; Inflammatory; Leukocytes; Ligands; Ligation; Liver; Lung; Maintenance; Manuscripts; Mediating; Membrane Microdomains; Microarray Analysis; Organogenesis; Pathway interactions; Play; Protein Family; Protein Kinase C; Publications; Receptor Activation; Receptor Signaling; Recombinants; Regulation; Reporting; Rest; Rodent; Role; Signal Pathway; Signal Transduction; Structure; Surface; System; T-Lymphocyte; Thymus Gland; Time; Tissues; Virus; Wnt proteins; Work; Writing; beta catenin; blastomere structure; cell motility; cell type; chemokine; chemokine receptor; in vivo; klotho protein; lymph nodes; member; migration; novel; protein expression; receptor; receptor expression; response; seven-transmembrane G-protein-coupled receptor; trafficking

Chemokines have been shown to induce and direct adhesion, chemotaxis, activation, and degranulation of human and rodent leukocytes both in vitro and in vivo. CXCL12 and CCL19 are two important chemokines that regulate T cell motility and activation under normal and inflammatory conditions. Despite numerous reports examining the function of chemokines, little is known about the transcriptional events involved therein. We have recently performed microarray analysis on CXCL12- and CCL19-treated T-cells, and found that the Wnt family of proteins was significantly upregulated during CXCL12 treatment. In the CXCL12 studies, we found that the expression of Wnt5A and other members of the non-canonical Wnt pathway were specifically upregulated during ligand stimulation of T cells, while beta-catenin and canonical Wnt family members were selectively downregulated. Wnt5A was found to augment signaling through the CXCL12-CXCR4 axis via the activation of protein kinase C (PKC). Moreover, our data has revealed that Wnt5A expression is required to mediate directional T-cell migration in response to CXCL12, and that the treatment of human T-cells with recombinant Wnt5A sensitized T-cells to CXCL12-induced migration. Furthermore,Wnt5A expression was also required for the sustained expression of CXCR4, both transcriptionally and translationally. Interestingly, in CCL19-treated T cells, we found that Wnt10A, not Wnt5A plays a role in CCL19-mediated chemotaxis and in the maintenance of CCR7 expression on T cells. We have recently found that T cells express the Klotho protein and the expression of Klotho in immune cells declines with age. We have found that over-expression of T cell Klotho levels diminishes T-cell Wnt expression and also diminishes chemokine receptor expression. In contrast, knockdown of T cell Klotho expression in T cells resulted in increases in Wnt5a and Wnt10A levels and chemokine receptor expression. This work has recently been completed and several manuscripts on these data are being written up for possible publication. These findings may reveal a novel cooperative signaling network between various chemokine and Wnt receptors and ligands that may control cell polarization and directional migration. Moreover, under these studies, we have also been verifying and characterizing several additional gene families that are highly expressed in T cells after migration in response to or simply stimulation with CXCL12, CCL19, gp120 and HIV-1 virus. Moreover, the role of lipid rafts in chemokine biology and HIV infectivity are also under examination using microarray analysis. A greater understanding of the transcriptional signals differentially induced by the ligation of various chemokine receptors may provide a means to dissect the pathways by which these chemoattractants induce cell migration and activation as well as any host transcriptional signals important in HIV entry and replication. This is relevant as modulation of Wnt expression in T cells modulates the HIV-1 infectivity of a cell through the regulation of relevant chemokine co-receptor expression.

趋化因子在体外和体内都能诱导和指导人和啮齿动物白细胞的黏附、趋化、激活和脱颗粒。CXCL12和CCL19是两种重要的趋化因子，在正常和炎症条件下调节T细胞的运动和激活。尽管有许多研究趋化因子功能的报道，但对其中涉及的转录事件知之甚少。我们最近对CXCL12和CCL19处理的T细胞进行了微阵列分析，发现Wnt蛋白家族在CXCL12处理过程中显著上调。在CXCL12的研究中，我们发现在T细胞的配体刺激过程中，Wnt5A和其他非典范Wnt途径成员的表达特异性上调，而β-连环素和典型Wnt家族成员的表达选择性下调。研究发现，WNT5A通过激活蛋白激酶C(PKC)，通过CXCL12-CXCR4轴增强信号传导。此外，我们的数据显示，在CXCL12的反应中，Wnt5A的表达是介导T细胞定向迁移所必需的，并且重组Wnt5A处理人T细胞会使T细胞对CXCL12诱导的迁移敏感。此外，CXCR4在转录和翻译上的持续表达也需要Wnt5A的表达。有趣的是，在CCL19处理的T细胞中，我们发现Wnt10A而不是Wnt5A在CCL19介导的趋化作用和维持T细胞上CCR7的表达方面发挥作用。我们最近发现T细胞表达Klotho蛋白，免疫细胞中Klotho蛋白的表达随着年龄的增长而下降。我们发现，T细胞Klotho水平的过度表达会减少T细胞Wnt的表达，也会减少趋化因子受体的表达。相反，T细胞Klotho表达下调导致Wnt5a和Wnt10A水平升高，趋化因子受体表达增加。这项工作最近已经完成，关于这些数据的几份手稿正在撰写中，可能会出版。这些发现可能揭示了多种趋化因子与Wnt受体和配体之间的新的合作信号网络，该网络可能控制细胞极化和定向迁移。此外，在这些研究中，我们还验证和表征了其他几个基因家族，这些基因家族在T细胞迁移后高表达，对CXCL12、CCL19、gp120和HIV-1病毒的反应或简单刺激。此外，脂筏在趋化因子生物学和艾滋病毒感染性中的作用也正在通过微阵列分析进行检查。更好地理解不同趋化因子受体连接诱导的转录信号可能提供一种手段来剖析这些趋化因子诱导细胞迁移和激活的途径，以及任何在HIV进入和复制中重要的宿主转录信号。这是相关的，因为T细胞中Wnt表达的调节通过调节相关趋化因子共受体的表达来调节细胞的HIV-1感染性。